Advanced Pharmacology-I (PHR5001) Lecture 2: Drug Development

1. Advanced Pharmacology-I(PHR5001)Lecture 2:Drug Development Dr. M G Azam Asstt. Professor Dept. of Pharmacy, NSU

2. Drug Development Process • Discovery and formulation:Synthesis of a potential new drug molecule and an understanding of its interaction (mechanism) with the appropriate biologic targets. Repeated application of this approach leads to compounds with increased potency and selectivity • Preclinical evaluation: Relevant biologic effects, drug metabolism, and pharmacokinetic profiles and particularly an assessment of the relative safety of the drug must be characterized in animals before human drug trials can be started. • Clinical evaluation -Phases I-IV: With regulatory approval, human testing can then go forward in three phases before the drug can be considered for approval for general use.

3. Basic Disciplines of Drug Development • Chemistry, Manufacturing, and Controls – Discovery (serendipity, folk medicine, random screening, rational drug design) – Chemistry (synthesis, purification, scale-up) – Analytical (chemical structure and activity, excipients, purity and stability) – Pharmaceutical (dosage form, route of administration, packaging and labeling) – Good Manufacturing Practice (GMP): • Guidelines related to manufacturing practices and specifications • Focus on impurities • Necessary to ensure quality of drug product (finished dosage form) and drug substance (bulk ingredients)

4. Basic Disciplines of Drug Development • Nonclinical – Testing in laboratory (in vitro) and in animal models (in vivo) to assess safety and efficacy – Objectives: • To develop the pharmacological profile • To determine the acute toxicity in at least 2 animal species • To assess toxicity with studies ranging from 2 weeks to several months – Good Laboratory Practice (GLP): • Guidelines related to studies in animal models • To ensure the quality and integrity of data by establishing basic standards for the conduct and reporting of nonclinical safety studies

5. Basic Disciplines of Drug Development • Clinical Investigation – Submission of the Investigative New Drug (IND, a request for permission from FDA to begin testing) – Conduct of Clinical Studies of the product in humans (in healthy volunteers or in patients) • Phase 1 • Phase 2 • Phase 3 • Phase 4 (post-marketing studies) Takes an average of 6 years to complete the first three stages

7. Drug Development Process A view on the process from the idea to the registered pharmaceutical • I. DISCOVERY • Drug discovery is the process by which new candidate medicationsare discovered. • Identification of target and resource

8. I. DISCOVERY • Target identification • - Area of interest in terms of drug indication ? • - Relevant cellular or molecular targets ? • - Appropriate assays – established or to be developed ? • Available relevant literature ? • Patent situation in the target area ? Resource identification Potential resources for novel drugs: - Natural organisms (plants, fungi, bacteria, animals) - Combinatorial chemistry - Structure-based drug design Methods for drug discovery: - High throughput screening (HTS) of random samples : large libraries of chemicals are tested for their ability to modify the target. For example, if the target is a novel GPCR, compounds will be screened for their ability to inhibit or stimulate that receptor . - Ethnobiological approach: Traditional use of natural organisms for medicines

9. Identification of drug targets

10. I. DISCOVERY Resource identification - Natural organisms, in particular plants - 52% of the drugs approved in the U.S. from 1981-2002 were natural products or derived from them - 26plant based drugs were approved during 2000-2006, including novel-molecular based drugs - In the future multicomponent botanical therapeutics will experience an increasing interest in biomedicine Medicinal plants continue to play a significant role as a resource for the discovery of novel drugs. Method of drug discovery - Ethnobotanical approach Systematic screening of: - Published literature on traditional medicinal plant use (e.g. documented traditional healers‘ experience) Advantages: - Preselection of potentially active resources - Promising safety profile (age-long experience) - Cost-efficient and comparatively fast

13. II. HIT GENERATION: RESEARCH AND DEVELOPMENT Process development – in phytopharmacy Herbal raw material Extraction solvent Extraction Miscella (Liquid raw extract) Development of the test substance Define: - Active substance (in phytopharmacy: native extract) - Dosage form Establish: - Physico-chemicalprofile (pKa, and solubility; permeability) of active compounds Investigate: - Pharmacology, - Mode of action Dry extract Liquid extract, tincture Encapsulatable mass Tablets, hard capsules Liquids, drops, ointments Soft capsules

14. II. HIT GENERATION: RESEARCH AND DEVELOPMENT • Preclinical development • In vitro profiling: • Biochemical assays (e.g. enzyme activity assays) • Cell culture assays (e.g. cancer cell lines) • Isolated tissue assays (e.g. mucosa model) • In vitro toxicology: • Investigate potential toxic effects • in bacteria- or cell cultures

15. What is a Preclinical Trial/Testing? • Preclinical trial - a laboratory test of a new drug or a new medical device, usually done on animal subjects, to see if the hoped-for treatment really works and if it is safe to test on humans. • Many preclinical tests include pharmacokinetics - the study of how drugs move through living organisms. • Four processes are examined in pharmacokinetic studies: absorption, distribution, metabolism, & excretion • Other tests include chemistry tests on purity, stability, and shelf life of product, as well as development studies on dosing, packaging, & administration (tablet, injection, etc…)

16. III. LEAD GENERATION: RESEARCH AND DEVELOPMENT Preclinical development In vivo testingAnimal model (mouse or rat) Drug action: - Behaviour and reaction - Physiology - Histopathology Toxicology: - Acute toxicity - Subchronic toxicity - Tissue specific toxicity - Tolerability Consider ethical aspects (e.g. number and kind of animals used) long-term carcinogenic effects or toxic effects on mammalian reproduction Heart, lungs, brain, kidney, liver and digestive system Objectives: To develop the pharmacological profile • To determine the acute toxicity in at least 2 animal species • To assess toxicity with studies ranging from 2 weeks to several months

20. III. LEAD GENERATION: RESEARCH AND DEVELOPMENT Preclinical development (continued) Pharmacokinetic studiesWhat does the body to the drug ? Investigate: - Liberation - Absorption - Distribution - Metabolism - Excretion Pharmacodynamic studiesWhat does the drug to the body ? Investigate: - Physiological effects - Drug action - Relationship between drug concentration & effect The main goals of pre-clinical studies are to determine a product's ultimate safety profile

21. Steps in Doing a Pre-Clinical Trial • Drugs usually act on either cellular or genetic chemicals in the body, known as targets, which are believed to be associated with disease. • Scientists use a variety of techniques to identify and isolate individual targets to learn more about their functions and how they influence disease. • Compounds are then identified that have various interactions with the drug targets that might be helpful in treatment of a specific disease. Step One: Get an idea for a drug target.

22. Steps in Doing a Pre-Clinical Trial Step Two: Develop a BioassayA Bioassay is a “live” system that can be used to measure drug effect. • It may be a culture of cells or organs or a whole animal. For example: • Zebra-fish embryos - you can see effects of drugs on bone density, blood vessel growth and many other systems of the zebra-fish.

23. Steps in Doing a Pre-Clinical Trial Step Three: Screen the drug in the Bioassay. • This is the actual test of the drug on the chosen bioassay. • This will determine if the drug is SAFE and if it is EFFECTIVE in the bioassay (BEFORE it is ever tested on humans!)

24. Step Four: Establish what dosage amount of the drug is safe and what dosage amount of the drug is toxic. • Most drugs have a toxic level or an amount at which the drug will becomeharmful instead of helpful. IND must show how the drug: • Is manufactured. • Appears (color, solubility, melting point, particle size, moisture content). • Formulated (pills, liquid, etc. + inactive ingredients). • Will be analyzed for purity, concentration, stability. • Will be tested for safety (this will be the basis for allowing first use in humans). Step Five: Application is made to the Food and Drug Administration (FDA) as an Investigational New Drug (IND).

25. Preclinical Information Required Before A Selected Drug Candidate Can Be Administered To Humans Pharmacological activity Pharmacokinetics and drug metabolism Toxicology Pharmaceutics Decision to proceed to man only after thorough characterisation of dose/concentration response relationships of candidate compound in vitro and in vivo

26. PHARMACOKINETICS AND DRUG METABOLISM PK of drug in rodents, dogs and primates as predictor of the human situation PK in animals is an essential part of drug selection to define the desired kinetic profile for a drug eg. half-life and bioavailability

27. Pharmacokinetics in Preclinical Species Single dose administration, IV & P.O. in safety species and pharmacology model (usually rat, dog, monkey) Purpose Ensure good bioavailability and exposure in safety assessment species to enable further evaluation in safety assessment studies (adequate exposure margins for human studies) Utilize data for prediction of human PK Understand the relationship between PK and efficacy in animals Data Obtained Area under the Curve (AUC, µM·hr): Area under the plasma concentration-time curve – reflects exposure Bioavailability (F, %): fraction of drug entering systemic circulation Clearance (CLp, mL/min): vol of plasma cleared of drug per unit time Volume of Distribution (Vd, L/Kg): measure of drug distribution in body Half life (t1/2, hr): time taken for the drug concentration in plasma to be reduced by half. Cmax, Tmax: maximum plasma concentration; time to reach maximum plasma concentration

28. Challenges and opportunities in Early Clinical Drug Development Understand the drug in context of; the disease How to measure The chemistry/pharmacology What causes the disease How does the disease evolve the patient What different phenotypes exists Are there different Genetic profiles

29. Preclinical Testing • Assess primary safety, biological activity, and therapeutic ratio • In vivo animal models • In vitro physiological models • 1 in 10,000 compounds pass • 3.5- 4 years to develop compound

30. Review: Steps to New Drug DiscoveryPre-Clinical Trials Get idea for drug target Develop a bioassay Screen chemical compounds in assay Establish effective and toxic amounts File for approval as an Investigational New Drug (IND) (leads to clinical trials)

31. Lecture 3: Clinical Trials & Drug Safety Assessment

32. Purpose Clinical Trials Clinical trials are a process of testing products prior to approval of a drug or treatment plan for widespread use in humans. • Is drug SAFE AND EFFECTIVE??? • Predict Toxic Effects • Determine Safe Dosage • Determine efficacy (effectiveness)

33. Phase I Clinical Trials • Determine primary safety and the maximum-tolerated dose in humans • Usually involve a single administration of the product or a placebo • Normal, healthy volunteers (20-100) • identify side effects • Usually last 6 months to 1 year (30% of drugs fail Phase 1 testing) • Determine ADME and pharmacological action of drug in humans

34. FACTORS TO BE CONSIDERED IN DECIDING THE STARTING DOSE FINDINGS LIKELY TO LEAD TO PROJECT TERMINATION Poor tolerability at therapeutic concentrations Unsatisfactory kinetics/metabolism Low potency Absence of efficacy • Maximum no effect dose/exposure in toxicity studies using most sensitive species • Nature & severity of toxicity seen in animals • Slope of dose-response curve PK REASONS FOR STOPPING DRUG DEVELOPMENT • Half-life (t ½) too short or too long • Poor bioavailability • Inconsistent bioavailability with low therapeutic index

35. Phase II Clinical Trials • Evaluate effectiveness, examine adverse effects, and select optimal dose • Involve patients who have the indicated disease or condition • – Small patient population (100-300) • – Usually last 2 years (37% of drugs fail Phase 2 testing) Study design: - Dosage comparison

36. Phase III Clinical Trials • Large-scale studies aimed at verifying efficacy establishing long-term safety & establish optimal dose and establishing the optimum dosage • monitor side effects • compare it to commonly used treatments • Interactions (with other meds) – Involve a larger number of patients (500-2000) – Usually last 3 years (6% fail Phase 3 testing) - Apply for a New Drug Application (NDA): 80% of an NDA is clinical data. About 80% of drugs that make it to Phase III studies get approved Study design: Comparison to placebo or to standard therapy Overall aim of Phase III: Risk-benefit evaluation

37. Phase IV Clinical Trials • Post-marketing surveillance • Long-term safety and efficacy in large patient populations • New indications for use • Special disease-state and populations • Drug interaction studies • Pharmacoeconomic studies

38. Phase IV • after the drug or treatment has been marketed • collect information about their effect in various populations • side effects associated with long-term use. • New indications: important for company to extend its patent protection. • Eg. Prozac – antianxiety, approved recently for PMDD (premenstrual dysorphic disorder) • Pharmacovigilance is the science of collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effects of medicines, biological products, herbals and traditional medicines with a view to: • Identifying information about potential new hazards • Preventing harm to patients.

39. Timeline for Discovery and Development A. Laboratory and animal studies 6 yrs B. File Investigational New Drug (IND) to FDA C. Phases I- III 7 years D. File New Drug Application (NDA) at FDA: 1.5 years E. Phase IV (post approval) 6 years

40. Allocation of time(in years)

41. The development and testing process required to bring a drug to market

44. Drug SafetyAssessment Drug safetyassessmentis an important goal in the drugdevelopment and Post Marketing Surveillance (PMS) It contributes to the balance of benefits and risks of the product It consists generally in anticipating, assessing and minimizing the cases of adverse drug reactions. Ateachstep of the drugdevelopment Preclinical Phase 1, 2-3 PMS (Post Marketing Surveillance) Mainlybased on SpontaneousReporting Systems

45. Drug Safety Assessment Objective : to assess toxicity in animal Acute toxicity (LD50, …) Subchronic toxicity (13 / 26 weeks) Chronic toxicity and cancerogenesis Reproductive testing Pre clinical studies Phase 1 clinical studies • Objective • Assess safety or toxicity (depending on compound) • Define therapeutic window / Maximum Tolerated Dose • Available data • Few volunteers (or patients) / dose escalating process • Thorough clinical assessment

46. Drug SafetyAssessmentPhase 2-3 Objective : to assess safety of study drug in larger studies in patients vs. placebo or reference drug General safety parameters Adverse events (AE) / serious adverse events (SAE) Biology / Biochemistry / ECG / Vital signs, … Disease / class specific safety parameters e.g. CV safety in diabetes • Statistical analysis (adverse events) • Descriptive tables (counts, crude incidence, incidence rate, …) • Number of AE (NAE) in a givenprimary system organ class • Number of patients (n) withat least one AE in a givenpreferredterm or a givenprimary system organ class • NumberNeeded To Harm (NNTH)

47. The End